This is a renewal application aimed at investigating the epigenetic pathways through which botanicals used commonly as CAM, suppress inflammation. During the previous funding cycle, we have made outstanding progress identifying novel cellular and molecular pathways through which botanicals mediate their anti- inflammatory properties. Inflammation can trigger a wide range of diseases including autoimmune, cardiovascular, neurodegenerative, obesity, and certain types of cancer. For this reason, it is not only critical to uncover as-yet-unknown immune mechanisms and mediators of inflammation but also find novel treatment modalities. Because currently there are no medications that can effectively treat chronic inflammation and associated pain without significant side effects, our proposed studies are highly significant. Traditionally, the medicine practiced in India (Ayurveda) and China have used herbal products to treat inflammatory disorders. Also, more than 25% of the pharmaceuticals are derived from plants, which suggests that botanicals offer novel modalities against inflammation. Epigenetic modifications of chromatin and DNA have been shown recently to play a critical role in the regulation in human pathologies, including inflammation. Thus, the concept that botanicals used as CAM may mediate their effects through epigenetic regulation is highly innovative. The primary objective of the Center is to test the overarching hypothesis that botanicals currently used as CAM, regulate the epigenetic signaling pathways through interactions with specific receptors on immune cells to modulate gene expression leading to amelioration of inflammation. This will be tested using four research projects, 1) Identifying epigenetic pathways through which resveratrol (RES) triggers myeloid- derived suppressor cells (MDSCs) in the regulation of neuroinflammation. 2) Epigenetic regulation of Nrf2 signaling pathway in American ginseng (AG)-mediated suppression of inflammation in the colon and colon cancer. 3) Elucidation of the epigenetic mechanisms underlying dietary indole-mediated amelioration of inflammation in the colon specifically addressing how indoles activate AhR to promote Tregs and suppress Th17 cells. 4) Identifying the role of Sparstolonin B (a compound isolated from Sparganium stoloniferum tubers), as a TLR2 and TLR4 antagonist, thereby suppressing inflammation in the liver through epigenetic regulation. The projects are highly integrated and synergistic, all addressing epigenetic pathways so that the data generated from one project will benefit other projects. The projects will use an Administrative Core which will coordinate all activities of the Center and ensure scientific and programmatic progress. All projects will also use an Analytical Core which will perform genome-wide DNA methylation, histone methylation/acetylation, microRNA arrays, immune monitoring, bioinformatics and natural product integrity testing. Together, our CAM Center will identify epigenetic biomarkers and pathways through which botanicals suppress inflammation thereby paving the way for better treatment modality against inflammatory diseases.